Elevated homocysteine would also be involved in another condition associated with MS-osteoporosis. Osteoporosis, which means “porous bone”, is a disease depicted by an increased risk of fractures due to weak bones. Osteoporosis can cause pain in many areas of the body, especially joints such as wrist, hip, and ankle. In the following study the researchers stated that osteoporosis and fractures are “extremely common” in the MS population.
International Journal of MS Care Volume 2, Issue 2 June 2000.
Osteoporosis in multiple sclerosis: a frequent, serious, and under-recognized problem.
Robert M. Herndon , MD, and Nirupa Mohandas , MD
“Osteoporosis and fractures are extremely common in the multiple sclerosis (MS) population, especially in those women with MS who are postmenopausal and not on hormone replacement therapy (HRT)…”
In the next study the researchers concluded that low bone mass is prevalent in ambulatory multiple sclerosis (MS) patients even shortly after clinical onset.
PLoS ONE;Sep2012, Vol. 7 Issue 9, Special section p1
Bone turnover and metabolism in patients with early multiple sclerosis and prevalent bone mass deficit: a population-based case-control study.
Moen, Stine Marit; Celius, Elisabeth Gulowsen; Sandvik, Leiv; Brustad, Magritt; Nordsletten, Lars; Eriksen, Erik Fink; Holmøy, Trygve; Oreja.-Guevara, Celia
“Low bone mass is prevalent in ambulatory multiple sclerosis (MS) patients even shortly after clinical onset…”
Homocysteine has been established through numerous studies to be a “strong and independent risk factor” for osteoporosis. Homocysteine affects osteoporosis by interfering with collagen cross-linking, which results in a defective bone matrix.
The following study was part of The Framingham Osteoporosis Study funded by the National Institutes of Health. The age-adjusted risk for hip fracture was four times higher for men and nearly twice as high for women in the group with the highest homocysteine levels. The study authors stated, “homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture.”
Homocysteine as a predictive factor for hip fracture in older persons.
McLean, R.R., P.F. Jacques, J. Selhub, K.L. Tucker, E.J. Samelson, K.E. Broe, M.T.
Hannan, L.A. Cupples, D.P. Kiel. 2004. New Engl J Med 350(20):2042-9.
“The increased prevalence of osteoporosis among people with homocystinuria suggests that a high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture…These findings suggest that the homocysteine concentration... is an important risk factor for hip fracture in older persons.”
In the following study the researchers concluded that homocysteine appeared to be a strong and independent risk factor for osteoporotic fractures in older men and women.
Homocysteine levels and the risk of osteoporotic fracture.
van Meurs, J.B., R.A. Dhonukshe-Rutten, S.M. Pluijm, K. van der Klift, R. de Jonge,
J. Lindemans, L.C. de Groot, A. Hofman, J.C. Witteman,J.P. van Leeuwen, M.M.
Breteler, P. Lips,H.A. Pols, A.G. Uitterlinden. 2004. New Engl J Med 350(20):233-41.
“…An increased homocysteine level appears to be a strong and independent risk factor for osteoporotic fractures in older men and women.
In the following study from Morocco researchers found that homocysteine was “significantly higher” in the osteoporotic patient group than in control patients, and that homocysteine and vitamin B12 were independent risk factors for osteoporosis.
Relation of plasma total homocysteine, folate and vitamin B12 levels to bone mineral density in Moroccan healthy postmenopausal women.
Ouzzif, Z., K. Oumghar, K. Sbai, A. Mounach, M. El Derouiche, A. El Maghraoui.
2012. Rheumatol Int 32(1):123-8.
“…Plasma tHcy was significantly higher in the osteoporotic group…tHcy and vitamin B12 are independent risk factors for osteoporosis in Moroccan healthy postmenopausal women.”
Some Interesting Connections
Re: Some Interesting Connections
In the previous study the researchers stated: “Osteoporosis and fractures are extremely common in the multiple sclerosis (MS) population, especially in those women with MS who are postmenopausal and not on hormone replacement therapy (HRT)…”
Why would estrogen be protective against osteoporosis and heart disease as well?
Prior to menopause women have a reduced risk of heart disease compared with men the same age. After menopause, due to declining levels of estrogen, the risk of heart disease in women rises yearly until it is equal to that of a male. Research shows that the protective effects of estrogen are due to its ability to lower homocysteine. These research findings were officially recognized with a recently published statement of the Third National Health and Examination Survey (NHANES); “Higher estrogen status is associated with a decreased mean serum total homocysteine concentration-independent of nutritional status or muscle mass. It’s a dramatic demonstration of the relationship between estrogen and homocysteine concentrations,” stated a NHANES researcher (U.S. Department of Agriculture, 2002).
If elevated levels of homocysteine are involved in osteoporosis, then patients with osteoporosis should also have an increased risk of developing cardiovascular disease. In the following study the researchers stated that mounting biological and epidemiological evidence supports a link between osteoporosis and cardiovascular disease.
The link between osteoporosis and cardiovascular disease.
Farhat, G.N., J.A. Cauley. 2008. Clin Cases Miner Bone Metab. 5(1): 19–34. PMCID: PMC2781192
“Cardiovascular disease (CVD) and osteoporosis are common age-related conditions associated with significant morbidity, mortality, and disability…Traditionally, these two conditions were considered unrelated and their coexistence was attributed to independent age-related processes. However, an increasing body of biological and epidemiological evidence has provided support for a link between the two conditions that cannot be explained by age alone…Mounting biological and epidemiological evidence supports a link between the two diseases. Low bone mineral density (BMD) has been related to increased cardiovascular mortality, cardiovascular morbidity, and subclinical measures of atherosclerosis in cross-sectional as well as longitudinal epidemiologic studies…”
Why would estrogen be protective against osteoporosis and heart disease as well?
Prior to menopause women have a reduced risk of heart disease compared with men the same age. After menopause, due to declining levels of estrogen, the risk of heart disease in women rises yearly until it is equal to that of a male. Research shows that the protective effects of estrogen are due to its ability to lower homocysteine. These research findings were officially recognized with a recently published statement of the Third National Health and Examination Survey (NHANES); “Higher estrogen status is associated with a decreased mean serum total homocysteine concentration-independent of nutritional status or muscle mass. It’s a dramatic demonstration of the relationship between estrogen and homocysteine concentrations,” stated a NHANES researcher (U.S. Department of Agriculture, 2002).
If elevated levels of homocysteine are involved in osteoporosis, then patients with osteoporosis should also have an increased risk of developing cardiovascular disease. In the following study the researchers stated that mounting biological and epidemiological evidence supports a link between osteoporosis and cardiovascular disease.
The link between osteoporosis and cardiovascular disease.
Farhat, G.N., J.A. Cauley. 2008. Clin Cases Miner Bone Metab. 5(1): 19–34. PMCID: PMC2781192
“Cardiovascular disease (CVD) and osteoporosis are common age-related conditions associated with significant morbidity, mortality, and disability…Traditionally, these two conditions were considered unrelated and their coexistence was attributed to independent age-related processes. However, an increasing body of biological and epidemiological evidence has provided support for a link between the two conditions that cannot be explained by age alone…Mounting biological and epidemiological evidence supports a link between the two diseases. Low bone mineral density (BMD) has been related to increased cardiovascular mortality, cardiovascular morbidity, and subclinical measures of atherosclerosis in cross-sectional as well as longitudinal epidemiologic studies…”
Re: Some Interesting Connections
MS is also associated with chronic obstructive pulmonary disease (COPD). Researchers in the following study discovered there was a more than two-fold increased risk of MS in patients with chronic obstructive pulmonary disease (COPD), a progressive lung disease that makes it hard to breathe. In COPD, the small capillaries that run through the walls of the air sacs in the lungs are damaged or completely destroyed. Symptoms of COPD include coughing that produces large amounts of mucus, wheezing, shortness of breath, and chest tightness. The researchers concluded their results indicate that COPD and MS have an “inflammatory vulnerability” in common and may share inflammatory pathways.
Lung. 2008 May-Jun;186(3):173-8. doi: 10.1007/s00408-008-9081-y. Epub 2008 Mar 20.
Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study.
Egesten A, Brandt L, Olsson T, Granath F, Inghammar M, Löfdahl CG, Ekbom A.
“…In the COPD cohort, there was a more than twofold increased risk of MS compared with controls… This study indicates that COPD and MS have an inflammatory vulnerability in common...These diseases may share inflammatory pathways…”
Homocysteine would be the “inflammatory vulnerability” that both COPD and MS patients share. In the following study the researchers found that homocysteine was significantly elevated in COPD patients and was related to serum C-reactive protein (CRP), a common inflammatory marker, and COPD severity.
Plasma homocysteine is elevated in COPD patients and is related to COPD severity.
Seemungal, T.A., J.C. Lun, G. Davis, C. Neblett, N. Chinyepi, C. Dookhan, S. Drakes, E.
Mandeville, F. Nana, S. Sethake, C.P. King, L. PintoPereira, J. Delisle, T.M. Wilkenson, J.A.
Wedzicha. 2007. Int J Chron Obstruct Pulmon Dis 2(3):313-21.
“…Plasma homocysteine is significantly elevated in COPD patients… and is related to serum CRP and COPD severity.”
Lung. 2008 May-Jun;186(3):173-8. doi: 10.1007/s00408-008-9081-y. Epub 2008 Mar 20.
Increased prevalence of multiple sclerosis among COPD patients and their first-degree relatives: a population-based study.
Egesten A, Brandt L, Olsson T, Granath F, Inghammar M, Löfdahl CG, Ekbom A.
“…In the COPD cohort, there was a more than twofold increased risk of MS compared with controls… This study indicates that COPD and MS have an inflammatory vulnerability in common...These diseases may share inflammatory pathways…”
Homocysteine would be the “inflammatory vulnerability” that both COPD and MS patients share. In the following study the researchers found that homocysteine was significantly elevated in COPD patients and was related to serum C-reactive protein (CRP), a common inflammatory marker, and COPD severity.
Plasma homocysteine is elevated in COPD patients and is related to COPD severity.
Seemungal, T.A., J.C. Lun, G. Davis, C. Neblett, N. Chinyepi, C. Dookhan, S. Drakes, E.
Mandeville, F. Nana, S. Sethake, C.P. King, L. PintoPereira, J. Delisle, T.M. Wilkenson, J.A.
Wedzicha. 2007. Int J Chron Obstruct Pulmon Dis 2(3):313-21.
“…Plasma homocysteine is significantly elevated in COPD patients… and is related to serum CRP and COPD severity.”
Re: Some Interesting Connections
In the following study the researchers discovered that patients with COPD had low levels of vitamin B12 and, as a consequence, increased homocysteine. The researchers concluded this may contribute to the COPD-related atherothrombotic risk. Atherothrombosis is the formation of a blood clot inside a blood vessel.
Hyperhomocysteinaemia and poor vitamin B status in chronic obstructive pulmonary
disease.
Fimognari, F.L., L. Loffredo, S. Di Simone, F. Sampietro, R. Pastorelli, M. Monaldo, F. Violi, A. D’Angelo. 2009. Nutr Metab Cardiovasc Dis. 19(9):654-9.
“Patients with chronic obstructive pulmonary disease (COPD) are at increased atherothrombotic risk. Preliminary findings have suggested that COPD patients may have increased plasma total homocysteine (tHcy), a cardiovascular risk factor often caused by a poor B vitamin status…COPD patients have a poor B vitamin status and, as a consequence,increased tHcy. These abnormalities may contribute to the COPD-related atherothrombotic risk.”
A lack of vitamin B12 is associated with white matter lesions-especially periventricular lesions.
The low levels of vitamin B12 found in COPD would lead to an increased risk of white matter lesions. The following study confirms that COPD is associated with periventricular white matter lesions.
Arterial oxygen saturation, COPD, and cerebral small vessel disease.
Van Dijk, E.J., S. Vermeer, J.C. de Groot, J. van de Minkelis, N. Prins, M. Oudkerk, A. Hofman, P. Koudstaal, and M. Breteler. 2004. J Neurol Neurosurg Psychiatry 75(5):733–736.
“…Participants with COPD had more severe periventricular white matter lesions than those without…Lower SaO2 and COPD are associated with more severe periventricular white matter lesions.”
B12 is necessary for the formation of myelin. In the next study the researchers concluded their results suggested a “specific association” between the timing of onset of the first neurological symptoms of MS and "vitamin B12 metabolism". The researchers also discussed the importance of vitamin B12 in the formation of myelin and stated that it’s deficiency in MS is of “critical pathogenetic significance.”
Vitamin B12 and its relationship to age of onset of multiple sclerosis.
Sandyk, R., G.I. Awerbuch. 1993. Int J Neurosci. 71(1-4):93-9.
“…these findings suggest a specific association between the timing of onset of first neurologicalsymptoms of MS and vitamin B12 metabolism. In addition, since vitamin B12 is required for the formation of myelin and for immune mechanisms, we propose that its deficiency in MS is of critical pathogenetic significance.”
In the following study the researchers concluded that vitamin B12 in the normal serum range was significantly associated with the severity of white-matter lesions, especially periventricular lesions.
Plasma vitamin B12 status and cerebral white-matter lesions.
de Lau, L.M., A.D. Smith, H. Refsum, C. Johnston, M.M. Breteler. 2009.
J Neurol Neurosurg Psychiatry 80(2) :149-57.
“… Poorer vitamin B12 status was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions, in a concentration-related manner… These results indicate that vitamin B12 status in the normal range is associated with severity of white-matter lesions, especially periventricular lesions…”
If the white matter lesions found in MS are indeed associated with a lack of vitamin B12, then a vitamin B12 deficiency should also be found in other diseases that present with white matter lesions. The following study demonstrates the presence of white matter lesions in Sjögren’s syndrome. Sjögren’s syndrome is an autoimmune disease that causes dryness in the eyes and mouth.
Cerebral white matter lesions in primary Sjögren’s syndrome:
a controlled study.
Coates, T., J.P. Slavotinek, M. Rischmueller, D. Schultz, C. Anderson, M. Dellamelva, M.R.
Sage, T.P. Gordon. 1999. J. Rheumatol. 26(6):1301-5.
“…There was a significant increase in lesions detected by MRI in SS patients versus controls…including deep white matter lesions… and subcortical white matter lesions…”
In the following study twenty-five percent of the Sjögren’s patients tested had low B12.
Iron and vitamin deficiencies, endocrine and immune status in patients with primary Sjögren’s syndrome.
Lundström, I.M., F.D. Lindström. 2001. Oral Dis. 7(3):144-9.
“…In total, current or previously treated iron and vitamin deficiencies were registered for 63% of the 1 degree SS patients…vitamin B12 25%...”
In addition, in the following study when fifty-eight Sjögren syndrome (SS) patients with neurologic manifestations associated with SS had magnetic resonance imaging (MRI) of the brain, the researchers found that 70% of the patients had white matter lesions and 40% met the radiologic criteria for MS.
Neurologic manifestations in primary Sjögren syndrome: a study of 82 patients.
Delalande, S., J. de Seze, A.L. Fauchais, E. Hachulla, T. Stojkovic, D. Ferriby, S. Dubucquoi, J.P. Pruvo, P. Vermersch, P.Y. Hatron. 2004. Medicine (Baltimore) 83(5):280-91.
“…We retrospectively studied 82 patients (65 women and 17 men) with neurologic manifestations associated with primary SS, as defined by the 2002 American-European criteria…Thirty-three patients had brain involvement and 13 patients had optic neuropathy. The disease mimicked relapsing-remitting multiple sclerosis (MS) in 10 patients and primary progressive MS in 13 patients… Thirty percent of patients (all with CNS involvement) had oligoclonal bands… Fifty-eight patients had magnetic resonance imaging (MRI) of the brain. Of these, 70% presented white matter lesions and 40% met the radiologic criteria for MS…”
Why do Sjogrens patients lack vitamin B12?
Research has found that the majority of Sjögren’s syndrome patients have “subclinical” (having no noticeable clinical symptoms) exocrine pancreatic insufficiency. Exocrine pancreatic insufficiency is the inability to properly digest food due to a lack of digestive enzymes. The exocrine pancreas is where protease and DNase I originate. Protease are essential for the binding and transport of vitamin B12.
In the following study the researchers identified subclinical exocrine pancreatic insufficiency in not only Sjögren’s syndrome, but in rheumatoid arthritis (RA) patients as well. In the Sjögren’s patients tested, 58.3% had a “significant decrease” in pancreatic enzymes.
Pancreatic duct antibodies and subclinical
insufficiency of the exocrine pancreas in Sjögren’s syndrome.
D’Ambrosi, A., A. Verzola, P. Buldrini, C. Vavalle, S. Panareo, S. Gatto, R. La Corte, L. Vicentini, A. Boccafogli, R. Scolozzi. 1998. Recenti Prog Med 89(10):504-9.
“In previous studies we reported evidence of subclinical exocrine pancreatic insufficiency in primary or secondary Sjögren’s syndrome (SSI, SSII) and rheumatoid arthritis (RA)…test results, compared to controls, showed a statistically significant decrease in duodenal juice volumes, bicarbonates and enzymes in 58.3% of SSI, and in 30% of RA…”
Hyperhomocysteinaemia and poor vitamin B status in chronic obstructive pulmonary
disease.
Fimognari, F.L., L. Loffredo, S. Di Simone, F. Sampietro, R. Pastorelli, M. Monaldo, F. Violi, A. D’Angelo. 2009. Nutr Metab Cardiovasc Dis. 19(9):654-9.
“Patients with chronic obstructive pulmonary disease (COPD) are at increased atherothrombotic risk. Preliminary findings have suggested that COPD patients may have increased plasma total homocysteine (tHcy), a cardiovascular risk factor often caused by a poor B vitamin status…COPD patients have a poor B vitamin status and, as a consequence,increased tHcy. These abnormalities may contribute to the COPD-related atherothrombotic risk.”
A lack of vitamin B12 is associated with white matter lesions-especially periventricular lesions.
The low levels of vitamin B12 found in COPD would lead to an increased risk of white matter lesions. The following study confirms that COPD is associated with periventricular white matter lesions.
Arterial oxygen saturation, COPD, and cerebral small vessel disease.
Van Dijk, E.J., S. Vermeer, J.C. de Groot, J. van de Minkelis, N. Prins, M. Oudkerk, A. Hofman, P. Koudstaal, and M. Breteler. 2004. J Neurol Neurosurg Psychiatry 75(5):733–736.
“…Participants with COPD had more severe periventricular white matter lesions than those without…Lower SaO2 and COPD are associated with more severe periventricular white matter lesions.”
B12 is necessary for the formation of myelin. In the next study the researchers concluded their results suggested a “specific association” between the timing of onset of the first neurological symptoms of MS and "vitamin B12 metabolism". The researchers also discussed the importance of vitamin B12 in the formation of myelin and stated that it’s deficiency in MS is of “critical pathogenetic significance.”
Vitamin B12 and its relationship to age of onset of multiple sclerosis.
Sandyk, R., G.I. Awerbuch. 1993. Int J Neurosci. 71(1-4):93-9.
“…these findings suggest a specific association between the timing of onset of first neurologicalsymptoms of MS and vitamin B12 metabolism. In addition, since vitamin B12 is required for the formation of myelin and for immune mechanisms, we propose that its deficiency in MS is of critical pathogenetic significance.”
In the following study the researchers concluded that vitamin B12 in the normal serum range was significantly associated with the severity of white-matter lesions, especially periventricular lesions.
Plasma vitamin B12 status and cerebral white-matter lesions.
de Lau, L.M., A.D. Smith, H. Refsum, C. Johnston, M.M. Breteler. 2009.
J Neurol Neurosurg Psychiatry 80(2) :149-57.
“… Poorer vitamin B12 status was significantly associated with greater severity of white-matter lesions, in particular periventricular white-matter lesions, in a concentration-related manner… These results indicate that vitamin B12 status in the normal range is associated with severity of white-matter lesions, especially periventricular lesions…”
If the white matter lesions found in MS are indeed associated with a lack of vitamin B12, then a vitamin B12 deficiency should also be found in other diseases that present with white matter lesions. The following study demonstrates the presence of white matter lesions in Sjögren’s syndrome. Sjögren’s syndrome is an autoimmune disease that causes dryness in the eyes and mouth.
Cerebral white matter lesions in primary Sjögren’s syndrome:
a controlled study.
Coates, T., J.P. Slavotinek, M. Rischmueller, D. Schultz, C. Anderson, M. Dellamelva, M.R.
Sage, T.P. Gordon. 1999. J. Rheumatol. 26(6):1301-5.
“…There was a significant increase in lesions detected by MRI in SS patients versus controls…including deep white matter lesions… and subcortical white matter lesions…”
In the following study twenty-five percent of the Sjögren’s patients tested had low B12.
Iron and vitamin deficiencies, endocrine and immune status in patients with primary Sjögren’s syndrome.
Lundström, I.M., F.D. Lindström. 2001. Oral Dis. 7(3):144-9.
“…In total, current or previously treated iron and vitamin deficiencies were registered for 63% of the 1 degree SS patients…vitamin B12 25%...”
In addition, in the following study when fifty-eight Sjögren syndrome (SS) patients with neurologic manifestations associated with SS had magnetic resonance imaging (MRI) of the brain, the researchers found that 70% of the patients had white matter lesions and 40% met the radiologic criteria for MS.
Neurologic manifestations in primary Sjögren syndrome: a study of 82 patients.
Delalande, S., J. de Seze, A.L. Fauchais, E. Hachulla, T. Stojkovic, D. Ferriby, S. Dubucquoi, J.P. Pruvo, P. Vermersch, P.Y. Hatron. 2004. Medicine (Baltimore) 83(5):280-91.
“…We retrospectively studied 82 patients (65 women and 17 men) with neurologic manifestations associated with primary SS, as defined by the 2002 American-European criteria…Thirty-three patients had brain involvement and 13 patients had optic neuropathy. The disease mimicked relapsing-remitting multiple sclerosis (MS) in 10 patients and primary progressive MS in 13 patients… Thirty percent of patients (all with CNS involvement) had oligoclonal bands… Fifty-eight patients had magnetic resonance imaging (MRI) of the brain. Of these, 70% presented white matter lesions and 40% met the radiologic criteria for MS…”
Why do Sjogrens patients lack vitamin B12?
Research has found that the majority of Sjögren’s syndrome patients have “subclinical” (having no noticeable clinical symptoms) exocrine pancreatic insufficiency. Exocrine pancreatic insufficiency is the inability to properly digest food due to a lack of digestive enzymes. The exocrine pancreas is where protease and DNase I originate. Protease are essential for the binding and transport of vitamin B12.
In the following study the researchers identified subclinical exocrine pancreatic insufficiency in not only Sjögren’s syndrome, but in rheumatoid arthritis (RA) patients as well. In the Sjögren’s patients tested, 58.3% had a “significant decrease” in pancreatic enzymes.
Pancreatic duct antibodies and subclinical
insufficiency of the exocrine pancreas in Sjögren’s syndrome.
D’Ambrosi, A., A. Verzola, P. Buldrini, C. Vavalle, S. Panareo, S. Gatto, R. La Corte, L. Vicentini, A. Boccafogli, R. Scolozzi. 1998. Recenti Prog Med 89(10):504-9.
“In previous studies we reported evidence of subclinical exocrine pancreatic insufficiency in primary or secondary Sjögren’s syndrome (SSI, SSII) and rheumatoid arthritis (RA)…test results, compared to controls, showed a statistically significant decrease in duodenal juice volumes, bicarbonates and enzymes in 58.3% of SSI, and in 30% of RA…”
Re: Some Interesting Connections
Homocysteine also activates microglia. Microglia are the resident macrophages of the central nervous system. In the following study the researchers stated that microglia participate in all phases of the MS disease process.
J Neurosci Res. 2005 Aug 1;81(3):363-73.
Microglia and multiple sclerosis.
Jack C, Ruffini F, Bar-Or A, Antel JP.
“Microglia participate in all phases of the multiple sclerosis (MS) disease process. As members of the innate immune system, these cells have evolved to respond to stranger/danger signals; such a response within the central nervous system (CNS) environment has the potential to induce an acute inflammatory response…”
In the following study the researchers stated that “microglial activation” in MS is thought to contribute directly to central nervous system damage through several mechanisms.
J Mol Med (Berl). 1997 Mar;75(3):165-73.
Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis.
Benveniste EN.
“One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.”
In the next study the researchers found that homocysteine promoted “proliferation and activation” of microglia. The researchers concluded, “Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”
Neurobiol Aging. 2010 Dec;31(12):2069-79. doi: 10.1016/j.neurobiolaging.2008.11.007. Epub 2009 Jan 7.
Homocysteine promotes proliferation and activation of microglia.
Zou CG, Zhao YS, Gao SY, Li SD, Cao XZ, Zhang M, Zhang KQ.
“Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway…Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”
J Neurosci Res. 2005 Aug 1;81(3):363-73.
Microglia and multiple sclerosis.
Jack C, Ruffini F, Bar-Or A, Antel JP.
“Microglia participate in all phases of the multiple sclerosis (MS) disease process. As members of the innate immune system, these cells have evolved to respond to stranger/danger signals; such a response within the central nervous system (CNS) environment has the potential to induce an acute inflammatory response…”
In the following study the researchers stated that “microglial activation” in MS is thought to contribute directly to central nervous system damage through several mechanisms.
J Mol Med (Berl). 1997 Mar;75(3):165-73.
Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis.
Benveniste EN.
“One of the characteristic features of microglia is their rapid activation in response to injury, inflammation, neurodegeneration, infection, and brain tumors. This review focuses on the role of the microglia in multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), and in the animal model of MS, experimental allergic encephalomyelitis (EAE). Microglial activation in MS and EAE is thought to contribute directly to CNS damage through several mechanisms, including production of proinflammatory cytokines, matrix metalloproteinases, and free radicals. In addition, activated microglia serve as the major antigen-presenting cell in the CNS, likely contributing to aberrant immune reactivity at this site. A mechanistic understanding of the way in which microglia are activated and ultimately inhibited is crucial for the formulation of therapeutic modalities to treat MS and other CNS autoimmune disease.”
In the next study the researchers found that homocysteine promoted “proliferation and activation” of microglia. The researchers concluded, “Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”
Neurobiol Aging. 2010 Dec;31(12):2069-79. doi: 10.1016/j.neurobiolaging.2008.11.007. Epub 2009 Jan 7.
Homocysteine promotes proliferation and activation of microglia.
Zou CG, Zhao YS, Gao SY, Li SD, Cao XZ, Zhang M, Zhang KQ.
“Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway…Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.”
Re: Some Interesting Connections
In the previous study the researchers concluded that homocysteine promoted the activity of NADPH oxidases which resulted in the generation of reactive oxygen species. Researchers in the following study concluded their study suggests that oxidative burst through reactive oxygen species production by NADPH oxidases is a major driving force for demyelination and neurodegeneration in multiple sclerosis lesions.
Oxidative burst is the rapid release of reactive oxygen species. Reactive oxygen species are chemically reactive molecules containing oxygen. Reactive oxygen species (ROS) form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of stress ROS levels can increase and result in significant damage to cell structures.
Brain. 2012 Mar;135(Pt 3):886-99. doi: 10.1093/brain/aws012.
NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.
Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H.
“…Our study suggests that oxidative burst through reactive oxygen species production by NADPH oxidases is a major driving force for demyelination and neurodegeneration in multiple sclerosis lesions.”
Oxidative burst is the rapid release of reactive oxygen species. Reactive oxygen species are chemically reactive molecules containing oxygen. Reactive oxygen species (ROS) form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of stress ROS levels can increase and result in significant damage to cell structures.
Brain. 2012 Mar;135(Pt 3):886-99. doi: 10.1093/brain/aws012.
NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury.
Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H.
“…Our study suggests that oxidative burst through reactive oxygen species production by NADPH oxidases is a major driving force for demyelination and neurodegeneration in multiple sclerosis lesions.”
Re: Some Interesting Connections
Homocysteine also interferes with intracellular magnesium metabolism.
In the following study the researchers discovered that patients with MS had significantly lower levels of magnesium (Mg) in erythrocytes (red blood cells).
Acta Neurol Scand. 1995 Jul;92(1):109-11.
Magnesium concentration in plasma and erythrocytes in MS.
Stelmasiak Z, Solski J, Jakubowska B.
“…A statistically significant decrease…of Mg concentration in erythrocytes and no changes in plasma of MS patients were found…”
Patients with MS were also found to have a “marked reduction” of magnesium (Mg) in central nervous system (CNS) white matter, including demyelinated plaques, in the next study. The patients also showed a significantly lower Mg content in central nervous system tissues and visceral organs such as liver, kidney, heart, and lung.
Acta Neurol Scand. 1990 Mar;81(3):197-200.
Magnesium concentration in brains from multiple sclerosis patients.
Yasui M, Yase Y, Ando K, Adachi K, Mukoyama M, Ohsugi K.
“…The magnesium contents were determined by inductively coupled plasma emission spectrometry in autopsy samples taken from 26 sites of central nervous system tissues, and visceral organs such as liver, spleen, kidney, heart and lung. The average Mg content in the CNS tissues, as well as visceral organs except for spleen, of MS patients showed a significantly lower value than that seen in control cases. The most marked reduction of Mg content was observed in CNS white matter including demyelinated plaques of MS samples…”
Researchers in the following study discovered that homocysteine (HC) causes a depletion of intracellular free magnesium by interfering with magnesium (Mg2+) metabolism. The study authors concluded, “The present findings are compatible with the hypothesis that an increased serum HC concentration causes abnormal metabolism of Mg2+…”
Extracellular magnesium regulates effects of vitamin B6, B12 and folate on homocysteinemia-induced depletion of intracellular free magnesium ions in canine cerebral vascular smooth muscle cells: possible relationship to [Ca2+]i, atherogenesis and stroke.
Wenyan, Li., T. Zheng, J. Wang, B.T. Altura, B.M. Altura. 1999. Neurosci Lett. 19 274 (2):83-6 10553943.
“The present findings are compatible with the hypothesis that an increased serum HC concentration causes abnormal metabolism of Mg2+ in cerebral VSMC, thus priming these cells for HC-induced atherogenesis, cerebral vasospasm and stroke.”
Magnesium is needed by the human body to carry out over 300 essential biochemical reactions. According to the National Institutes of Health, magnesium helps maintain normal muscle function and nerve function, keeps the heart rhythm steady, supports a healthy immune system, and keeps bones strong. Magnesium also helps regulate blood sugar levels, promotes normal blood pressure, and is known to be involved in energy metabolism and protein synthesis (National Institutes of Health, 2009).
Because magnesium is active in so many different processes in the body, magnesium deficiency symptoms are varied and can include: insomnia, muscle spasms, muscle twitches and soreness, difficulty swallowing, heart palpitations, extreme fatigue, back aches, chest tightness and difficulty breathing, osteoporosis, and dizziness.
In the following study the researchers discovered that patients with MS had significantly lower levels of magnesium (Mg) in erythrocytes (red blood cells).
Acta Neurol Scand. 1995 Jul;92(1):109-11.
Magnesium concentration in plasma and erythrocytes in MS.
Stelmasiak Z, Solski J, Jakubowska B.
“…A statistically significant decrease…of Mg concentration in erythrocytes and no changes in plasma of MS patients were found…”
Patients with MS were also found to have a “marked reduction” of magnesium (Mg) in central nervous system (CNS) white matter, including demyelinated plaques, in the next study. The patients also showed a significantly lower Mg content in central nervous system tissues and visceral organs such as liver, kidney, heart, and lung.
Acta Neurol Scand. 1990 Mar;81(3):197-200.
Magnesium concentration in brains from multiple sclerosis patients.
Yasui M, Yase Y, Ando K, Adachi K, Mukoyama M, Ohsugi K.
“…The magnesium contents were determined by inductively coupled plasma emission spectrometry in autopsy samples taken from 26 sites of central nervous system tissues, and visceral organs such as liver, spleen, kidney, heart and lung. The average Mg content in the CNS tissues, as well as visceral organs except for spleen, of MS patients showed a significantly lower value than that seen in control cases. The most marked reduction of Mg content was observed in CNS white matter including demyelinated plaques of MS samples…”
Researchers in the following study discovered that homocysteine (HC) causes a depletion of intracellular free magnesium by interfering with magnesium (Mg2+) metabolism. The study authors concluded, “The present findings are compatible with the hypothesis that an increased serum HC concentration causes abnormal metabolism of Mg2+…”
Extracellular magnesium regulates effects of vitamin B6, B12 and folate on homocysteinemia-induced depletion of intracellular free magnesium ions in canine cerebral vascular smooth muscle cells: possible relationship to [Ca2+]i, atherogenesis and stroke.
Wenyan, Li., T. Zheng, J. Wang, B.T. Altura, B.M. Altura. 1999. Neurosci Lett. 19 274 (2):83-6 10553943.
“The present findings are compatible with the hypothesis that an increased serum HC concentration causes abnormal metabolism of Mg2+ in cerebral VSMC, thus priming these cells for HC-induced atherogenesis, cerebral vasospasm and stroke.”
Magnesium is needed by the human body to carry out over 300 essential biochemical reactions. According to the National Institutes of Health, magnesium helps maintain normal muscle function and nerve function, keeps the heart rhythm steady, supports a healthy immune system, and keeps bones strong. Magnesium also helps regulate blood sugar levels, promotes normal blood pressure, and is known to be involved in energy metabolism and protein synthesis (National Institutes of Health, 2009).
Because magnesium is active in so many different processes in the body, magnesium deficiency symptoms are varied and can include: insomnia, muscle spasms, muscle twitches and soreness, difficulty swallowing, heart palpitations, extreme fatigue, back aches, chest tightness and difficulty breathing, osteoporosis, and dizziness.
Re: Some Interesting Connections
The following study was recently posted on the board.
BMC Neurol. 2011 Aug 3;11:95. doi: 10.1186/1471-2377-11-95.
Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes.
Pender MP, Csurhes PA, Pfluger CM, Burrows SR.
“Patients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells…The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population…In confirmation of previous studies we also found that the percentage of CD8+ T cells was significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio were significantly increased in patients with MS compared to healthy subjects.”
So, patients with MS have a a general CD8+T cell deficiency. CD8+T cells are cells that attack virus infected cells. Patients with MS also have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. In addition, the percentage of CD8+ T cells is significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio are significantly increased in patients with MS. To my knowledge, there has not been found an explanation for this.
In the following study the researchers concluded that vitamin B12 plays an important role in cellular immunity, "especially relating to CD8+ cells and the NK cell system."
Clin Exp Immunol. 1999 Apr;116(1):28-32.
Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment.
Tamura J, Kubota K, Murakami H, Sawamura M, Matsushima T, Tamura T, Saitoh T, Kurabayshi H, Naruse T.
“It has been suggested that vitamin B12 (vit.B12) plays an important role in immune system regulation, but the details are still obscure. In order to examine the action of vit.B12 on cells of the human immune system, lymphocyte subpopulations and NK cell activity were evaluated in 11 patients with vit.B12 deficiency anaemia and in 13 control subjects. Decreases in the number of lymphocytes and CD8+ cells and in the proportion of CD4+ cells, an abnormally high CD4/CD8 ratio, and suppressed NK cell activity were noted in patients compared with control subjects...These results indicate that vit.B12 might play an important role in cellular immunity, especially relating to CD8+ cells and the NK cell system, which suggests effects on cytotoxic cells. We conclude that vit.B12 acts as an immunomodulator for cellular immunity.”
BMC Neurol. 2011 Aug 3;11:95. doi: 10.1186/1471-2377-11-95.
Decreased CD8+ T cell response to Epstein-Barr virus infected B cells in multiple sclerosis is not due to decreased HLA class I expression on B cells or monocytes.
Pender MP, Csurhes PA, Pfluger CM, Burrows SR.
“Patients with multiple sclerosis (MS) have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells…The decreased CD8+ T cell response to EBV results from a general CD8+ T cell deficiency and also a decreased proportion of EBV-specific T cells within the total CD8+ T cell population…In confirmation of previous studies we also found that the percentage of CD8+ T cells was significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio were significantly increased in patients with MS compared to healthy subjects.”
So, patients with MS have a a general CD8+T cell deficiency. CD8+T cells are cells that attack virus infected cells. Patients with MS also have a decreased frequency of CD8+ T cells reactive to their own Epstein-Barr virus (EBV) infected B cells. In addition, the percentage of CD8+ T cells is significantly decreased whereas the percentage of CD4+ T cells and the CD4:CD8 ratio are significantly increased in patients with MS. To my knowledge, there has not been found an explanation for this.
In the following study the researchers concluded that vitamin B12 plays an important role in cellular immunity, "especially relating to CD8+ cells and the NK cell system."
Clin Exp Immunol. 1999 Apr;116(1):28-32.
Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment.
Tamura J, Kubota K, Murakami H, Sawamura M, Matsushima T, Tamura T, Saitoh T, Kurabayshi H, Naruse T.
“It has been suggested that vitamin B12 (vit.B12) plays an important role in immune system regulation, but the details are still obscure. In order to examine the action of vit.B12 on cells of the human immune system, lymphocyte subpopulations and NK cell activity were evaluated in 11 patients with vit.B12 deficiency anaemia and in 13 control subjects. Decreases in the number of lymphocytes and CD8+ cells and in the proportion of CD4+ cells, an abnormally high CD4/CD8 ratio, and suppressed NK cell activity were noted in patients compared with control subjects...These results indicate that vit.B12 might play an important role in cellular immunity, especially relating to CD8+ cells and the NK cell system, which suggests effects on cytotoxic cells. We conclude that vit.B12 acts as an immunomodulator for cellular immunity.”
-
grandsons4
- Family Member
- Posts: 87
- Joined: Wed Aug 14, 2013 6:43 pm
Re: Some Interesting Connections
This is a recapitulation of previous posts, but I believe relevant. It appears obvious that supplemention with B12, D, and zinc would be beneficial.
Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis.
Abstract
The shorter the interval between MS onset and our assays, the more intense was the EBV-specific CD8+ T-cell response. Confirming the above results, we found that EBV-specific CD8+ T-cell responses decreased in 12/13 patients with CIS followed prospectively for 1.0 +/- 0.2 years. In contrast, there was no difference between categories for EBV-specific CD4+ T cell, or for CMV-specific CD4+ and CD8+ T-cell responses. Anti-EBV-encoded nuclear antigen-1 (EBNA-1)-specific antibodies correlated with EBV-specific CD8+ T cells in patients with CIS and RR-MS. However, whereas EBV-specific CD8+ T cells were increased the most in early MS, EBNA-1-specific antibodies were increased in early as well as in progressive forms of MS. Our data show high levels of CD8+ T-cell activation against EBV--but not CMV--early in the course of MS, which support the hypothesis that EBV might be associated with the onset of this disease.
http://www.ncbi.nlm.nih.gov/pubmed/18550621
Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects.
Abstract
Little is known on a putative effect of vitamin D on CD8+ T cells. Yet, these cells are involved in the immmunopathogenesis of MS. We assessed the cytokine profile of EBV-specific CD8+ T cells of 10 early MS patients and 10 healthy control subjects with or without 1,25(OH)(2)D(3) and found that, with 1,25(OH)(2)D(3), these cells secreted less IFN-γ and TNF-α and more IL-5 and TGF-β. CD4+ T cell depletion or even culture with CD8+ T cells only did not abolish the immunomodulatory effect of 1,25(OH)(2)D(3) on CD8+ T cells, suggesting that 1,25(OH)(2)D(3) can act directly on CD8+ T cells.
http://www.ncbi.nlm.nih.gov/pubmed/21186064
Zinc suppresses Th17 development via inhibition of STAT3 activation. (Note: Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection.)
We have shown that Zn suppressed CIA development, decreased serum levels of IL-17A but not those of IFN-γ and
reduced the numbers of Th17 cells but not those of Th1 cells in regional lymph nodes.
Importantly, IL-6 induced STAT3 phosphorylation in CD4+ T cells was inhibited by Zn treatment
in vivo. Moreover, Zn suppressed Th17 cell development and IL-6-induced STAT3
phosphorylation in vitro. Collectively, these results strongly suggested that Zn suppresses Th17- cell development after the induction of CIA. Mechanistic analysis showed that Zn structurally
altered STAT3 to inhibit its activation after IL-6 stimulation. Thus, we conclude that Zn directly suppresses STAT3 activation, which in turn inhibits Th17-cell development.
http://m.intimm.oxfordjournals.org/cont ... 5/375.full
Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis.
Abstract
The shorter the interval between MS onset and our assays, the more intense was the EBV-specific CD8+ T-cell response. Confirming the above results, we found that EBV-specific CD8+ T-cell responses decreased in 12/13 patients with CIS followed prospectively for 1.0 +/- 0.2 years. In contrast, there was no difference between categories for EBV-specific CD4+ T cell, or for CMV-specific CD4+ and CD8+ T-cell responses. Anti-EBV-encoded nuclear antigen-1 (EBNA-1)-specific antibodies correlated with EBV-specific CD8+ T cells in patients with CIS and RR-MS. However, whereas EBV-specific CD8+ T cells were increased the most in early MS, EBNA-1-specific antibodies were increased in early as well as in progressive forms of MS. Our data show high levels of CD8+ T-cell activation against EBV--but not CMV--early in the course of MS, which support the hypothesis that EBV might be associated with the onset of this disease.
http://www.ncbi.nlm.nih.gov/pubmed/18550621
Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects.
Abstract
Little is known on a putative effect of vitamin D on CD8+ T cells. Yet, these cells are involved in the immmunopathogenesis of MS. We assessed the cytokine profile of EBV-specific CD8+ T cells of 10 early MS patients and 10 healthy control subjects with or without 1,25(OH)(2)D(3) and found that, with 1,25(OH)(2)D(3), these cells secreted less IFN-γ and TNF-α and more IL-5 and TGF-β. CD4+ T cell depletion or even culture with CD8+ T cells only did not abolish the immunomodulatory effect of 1,25(OH)(2)D(3) on CD8+ T cells, suggesting that 1,25(OH)(2)D(3) can act directly on CD8+ T cells.
http://www.ncbi.nlm.nih.gov/pubmed/21186064
Zinc suppresses Th17 development via inhibition of STAT3 activation. (Note: Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection.)
We have shown that Zn suppressed CIA development, decreased serum levels of IL-17A but not those of IFN-γ and
reduced the numbers of Th17 cells but not those of Th1 cells in regional lymph nodes.
Importantly, IL-6 induced STAT3 phosphorylation in CD4+ T cells was inhibited by Zn treatment
in vivo. Moreover, Zn suppressed Th17 cell development and IL-6-induced STAT3
phosphorylation in vitro. Collectively, these results strongly suggested that Zn suppresses Th17- cell development after the induction of CIA. Mechanistic analysis showed that Zn structurally
altered STAT3 to inhibit its activation after IL-6 stimulation. Thus, we conclude that Zn directly suppresses STAT3 activation, which in turn inhibits Th17-cell development.
http://m.intimm.oxfordjournals.org/cont ... 5/375.full
Re: Some Interesting Connections
.grandsons4 wrote:It appears obvious that supplemention with B12, D, and zinc would be beneficial
The problem with these nutrients is they are not being properly metabolized in MS. For instance, MS patients are unable to properly bind and transport vitamin B12, so would taking additional in supplement form solve this problem or would it actually increase your risk of disease? I posted some information in this thread on the increased risk of cancer from vitamin B12 supplements.
Protease are necessary for the binding and transport of vitamin B12. Protease are also necessary to properly bind and transport zinc and vitamin D.
In the following study the researchers concluded their results suggest that mechanisms which govern zinc cellular availability, compartmentalization of zinc, or the binding of zinc to cell surface membranes may be altered in patients with MS.
Ann Neurol. 1986 Dec;20(6):712-5.
Zinc in multiple sclerosis. II: Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis.
Ho SY, Catalanotto FA, Lisak RP, Dore-Duffy P.
“…Results suggest that mechanisms which govern cellular availability, compartmentalization of Zn, or the binding of Zn to cell surface membranes may be altered in patients with MS, and that these mechanisms vary with disease activity.”
Protease digest dietary proteins and release essential amino acids-one of which is histidine.
In the following study the researchers found an association between “subnormal” plasma histidine levels and impaired protein hydrolysis in patients with MS.
(Altern Med Rev 2000;5(3):224-248.)
Transdermal histamine in multiple sclerosis, part two: A proposed theoretical basis for its use.
George Gillson, MD, PhD,
Jonathan V. Wright, MD, Elaine DeLack, RN,
and George Ballasiotes, BSc, Pharm
“…Here we include preliminary findings on the impairments of digestion and assimilation in MS patients seen in a private clinic. Although only a small number of patients was surveyed, an association was found between impaired gastric acid production, impaired protein hydrolysis, and subnormal plasma histidine levels in patients with MS. Impaired digestion might, therefore, impair the ability of MS patients to synthesize histamine…Various mechanisms of action are suggested, including: enhanced gastric acid and pancreatic enzyme secretion…We also discuss the observed failure of digestive function in MS…”
The lack of the essential amino acid histidine found in patients with MS would explain the altered zinc metabolism. As the following study states, zinc utilizes an amino acid carrier system and is transported as a zinc-histidine complex.
J Physiol. 1992 January; 445: 69–80.
Effects of amino acids on zinc transport in rat erythrocytes.
S P Aiken, N M Horn, and N R Saunders
Department of Physiology & Pharmacology, University of Southampton.
“zinc is being transported as a zinc-histidine complex, utilizing an amino acid carrier system…”
Although zinc is an essential requirement for a healthy body, zinc, like iron, is a heavy metal ion and must be carefully controlled. Heavy metal ions are toxic to cells. Our bodies take great care to make sure metals go only where they need to and in exactly the right amount.
Scientists have discovered that metals, such as zinc, have special “chaperone” proteins that safely escort the metal through the interior of the cell and deliver it to the specific site where it is needed. Zinc also has “binding proteins” to prevent it from accumulating within the cell and poisoning the cell. The essential amino acid histidine, which is lacking in patients with MS, is an essential component of zinc binding proteins, such as ZntR and Zur.
According to Thomas O’Halloran, professor of chemistry at Northwestern University, “The zinc regulatory system is so sensitive and finely tuned-at the femtomolar level-that the metal ions have no chance to float freely in the cell’s cytoplasm before they are bound up in ZntR or Zur. Free floating zinc just doesn’t exist” (Northwestern University, 2001).
In the following study the researchers stated that although zinc is an essential trace element, excess zinc can cause neuronal death. In addition, the researchers concluded that histidine was protective against zinc-induced neurotoxicity.
Metallomics, 2013,5, 453-460
D-Histidine and L-histidine attenuate zinc-induced neuronal death in GT1-7 cells.
Masahiro Kawahara,*a Yutaka Sadakane,b Hironari Koyama,c Keiko Konohac and Susumu Ohkawarac
“Although zinc (Zn) is an essential trace element, excess Zn causes neuronal death following transient global ischemia and plays a central role in the pathogenesis of vascular-type dementia…both L-histidine and D-histidine exhibit the same neuroprotective activity…that histidine protects against Zn-induced neurotoxicity…”
We know that patients with MS already lack one of the essential components to prevent zinc toxicity, but science doesn’t fully understand the complexities involved in how the body protects itself from zinc, while at the same time benefitting from it, so taking isolated zinc in supplement form could prove harmful.
Re: Some Interesting Connections
Annesse, the problem is in the gut, in particular in the large intestine which is bacteria driven and for vitamine production and absorption and micronutitions absorption (the small intestine is enzyme driven and for the energy homeostasis). If things go wrong there, vitamines are not absorbed, regardless of supplementation. The question whether supplementation is good or bad is a relevant one. Probably more of the latter. It all communicates together, teh small intestine, the large intestine, the cells, in ways not understood. On the metalevel, fecal microbiota transplantation is a way to restore the health of the large intestine.
Re: Some Interesting Connections
I agree Leonard, the problem does begin in the gut-but I think specifically in the pancreas with missing enzymes that digest proteins and dietary DNA. (They do a few other things too, which we will be discussing.)
Elevated levels of homocysteine can also lead to excess nitric oxide (NO). In the following study from the Karolinska Institute, the institute that awards the Nobel prizes in medicine, the researchers found that NOx (nitrite) levels were significantly increased in MS. As the researchers explain, NOx is an oxidation product of NO and its concentration is used to determine production of NO. The study authors concluded their results supported the involvement of NO in the pathogenesis of MS.
J Neuroimmunol. 2003 Mar;136(1-2):112-8.
Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis.
Danilov AI, Andersson M, Bavand N, Wiklund NP, Olsson T, Brundin L.
“…Nitric oxide (NO) is formed as a consequence of induction of the iNOS enzyme during inflammatory disorders. To investigate NO production in multiple sclerosis (MS), we determined the concentrations of its oxidation products (NOx) in the cerebrospinal fluid (CSF) and plasma of 61 MS patients…The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls…CSF nitrite correlated with clinical disease activity. At exacerbation, the CSF nitrite levels exceed the plasma level. This suggests that clinical disease activity is due to a CNS inflammatory response, which is more intense and qualitatively different from that during clinical stable phases. This study supports NO involvement in the pathogenesis of MS…”
In the following study published in Neurology the researchers found that cerebrospinal fluid levels of NOx were increased in even mildly disabled MS patients and that this increase was associated with clinical and MRI progression in MS patients.
Neurology. 2004 Oct 26;63(8):1439-45.
CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis.
Rejdak K, Eikelenboom MJ, Petzold A, Thompson EJ, Stelmasiak Z, Lazeron RH, Barkhof F, Polman CH, Uitdehaag BM, Giovannoni G.
“To investigate the relationship of CSF and the serum nitric oxide metabolites nitrite and nitrate (NOx) to disease activity and progression in patients with multiple sclerosis (MS)…CSF nitrite and nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI. Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.”
In the next study published in the Journal of Neurology the researchers found a significant increase of nitrite and homocysteine and a decrease in vitamin B12 in all of the MS patients tested. The researchers stated that a “linear” relationship between the levels of nitrite and homocysteine was found, suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine.
Journal of Neurology
January 2008, Volume 255, Issue 1, pp 64-69
The interrelation between the deficiency of vitamin B12 and neurotoxicity of homocysteine with nitrite in some of neurologic disorders.
BAIG S. M. (1) ; ALI QURESHI G. (2) ; MINAMI M. (3) ;
“In this study, the relation between vitamin B12 deficiency and neurotoxicity of homocysteine with nitrite (a metabolite of nitric oxide) is defined on the basis of accumulated results obtained in cerebrospinal fluid from 20 parkinsons patients, 16 patients with cerebrovascular disorders, 20 patients with multiple sclerosis, 18 patients with aseptic meningitis and 14 patients with tuberculous meningitis. These results were compared with 14 healthy subjects. The results showed the significant increase of nitrite…and homocysteine, and decrease in vitamin B12 in all patients except patients with aseptic meningitis. A linear relationship between the CSF levels of nitrite and homocysteine was found, suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine…”
Elevated levels of homocysteine can also lead to excess nitric oxide (NO). In the following study from the Karolinska Institute, the institute that awards the Nobel prizes in medicine, the researchers found that NOx (nitrite) levels were significantly increased in MS. As the researchers explain, NOx is an oxidation product of NO and its concentration is used to determine production of NO. The study authors concluded their results supported the involvement of NO in the pathogenesis of MS.
J Neuroimmunol. 2003 Mar;136(1-2):112-8.
Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis.
Danilov AI, Andersson M, Bavand N, Wiklund NP, Olsson T, Brundin L.
“…Nitric oxide (NO) is formed as a consequence of induction of the iNOS enzyme during inflammatory disorders. To investigate NO production in multiple sclerosis (MS), we determined the concentrations of its oxidation products (NOx) in the cerebrospinal fluid (CSF) and plasma of 61 MS patients…The total levels of NOx in CSF were significantly increased in all MS groups as compared to healthy controls…CSF nitrite correlated with clinical disease activity. At exacerbation, the CSF nitrite levels exceed the plasma level. This suggests that clinical disease activity is due to a CNS inflammatory response, which is more intense and qualitatively different from that during clinical stable phases. This study supports NO involvement in the pathogenesis of MS…”
In the following study published in Neurology the researchers found that cerebrospinal fluid levels of NOx were increased in even mildly disabled MS patients and that this increase was associated with clinical and MRI progression in MS patients.
Neurology. 2004 Oct 26;63(8):1439-45.
CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis.
Rejdak K, Eikelenboom MJ, Petzold A, Thompson EJ, Stelmasiak Z, Lazeron RH, Barkhof F, Polman CH, Uitdehaag BM, Giovannoni G.
“To investigate the relationship of CSF and the serum nitric oxide metabolites nitrite and nitrate (NOx) to disease activity and progression in patients with multiple sclerosis (MS)…CSF nitrite and nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI. Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.”
In the next study published in the Journal of Neurology the researchers found a significant increase of nitrite and homocysteine and a decrease in vitamin B12 in all of the MS patients tested. The researchers stated that a “linear” relationship between the levels of nitrite and homocysteine was found, suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine.
Journal of Neurology
January 2008, Volume 255, Issue 1, pp 64-69
The interrelation between the deficiency of vitamin B12 and neurotoxicity of homocysteine with nitrite in some of neurologic disorders.
BAIG S. M. (1) ; ALI QURESHI G. (2) ; MINAMI M. (3) ;
“In this study, the relation between vitamin B12 deficiency and neurotoxicity of homocysteine with nitrite (a metabolite of nitric oxide) is defined on the basis of accumulated results obtained in cerebrospinal fluid from 20 parkinsons patients, 16 patients with cerebrovascular disorders, 20 patients with multiple sclerosis, 18 patients with aseptic meningitis and 14 patients with tuberculous meningitis. These results were compared with 14 healthy subjects. The results showed the significant increase of nitrite…and homocysteine, and decrease in vitamin B12 in all patients except patients with aseptic meningitis. A linear relationship between the CSF levels of nitrite and homocysteine was found, suggesting that the production of nitrite is interrelated with the neurotoxic level of homocysteine…”
Re: Some Interesting Connections
Nitric oxide regulates a potent vasoconstrictor called endothelin-1 (ET-1). In the following study the researchers found that ET-1 was significantly elevated in patients with MS and concluded that cerebral hypoperfusion (decreased cerebral blood flow) in MS is mediated by ET-1.
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5654-8. doi: 10.1073/pnas.1222560110. Epub 2013 Mar 18.
Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.
D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J.
“Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein…These data demonstrate that reduced CBF in MS is mediated by ET-1…”
In the following study the researchers found that ET-1 levels were, on average, 224% higher in patients with MS.
J Neuroophthalmol. 2001 Mar;21(1):37-8.
Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Haufschild T, Shaw SG, Kesselring J, Flammer J.
“We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients…The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease...The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.”
In the following study the researchers concluded that diminished NO bioavailability results in unmitigated ET-1 actions which lead to vasoconstriction and eventually to vascular dysfunction.
Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1288-95. doi: 10.1152/ajpregu.00397.2010. Epub 2011 Mar 2.
The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives.
“Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease…we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.”
In the following study the researchers concluded that homocysteine decreases bioavailable nitric oxide.
J Biol Chem. 1997 Jul 4;272(27):17012-7.
Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.
Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J.
“Hyperhomocysteinemia is believed to injure endothelial cells in vivo through a number of mechanisms…Hcy affects the bioavailability of NO…”
Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5654-8. doi: 10.1073/pnas.1222560110. Epub 2013 Mar 18.
Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1.
D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J.
“Decreased cerebral blood flow (CBF) may contribute to the pathology of multiple sclerosis (MS), but the underlying mechanism is unknown. We investigated whether the potent vasoconstrictor endothelin-1 (ET-1) is involved. We found that, compared with controls, plasma ET-1 levels in patients with MS were significantly elevated in blood drawn from the internal jugular vein and a peripheral vein…These data demonstrate that reduced CBF in MS is mediated by ET-1…”
In the following study the researchers found that ET-1 levels were, on average, 224% higher in patients with MS.
J Neuroophthalmol. 2001 Mar;21(1):37-8.
Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Haufschild T, Shaw SG, Kesselring J, Flammer J.
“We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients…The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean +/- standard deviation [SD]) were 3.5 +/- 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 +/- 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease...The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.”
In the following study the researchers concluded that diminished NO bioavailability results in unmitigated ET-1 actions which lead to vasoconstriction and eventually to vascular dysfunction.
Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1288-95. doi: 10.1152/ajpregu.00397.2010. Epub 2011 Mar 2.
The interaction between endothelin-1 and nitric oxide in the vasculature: new perspectives.
“Nitric oxide (NO) and endothelin-1 (ET-1) are natural counterparts in vascular function, and it is becoming increasingly clear that an imbalance between these two mediators is a characteristic of endothelial dysfunction and is important in the progression of vascular disease…we suggest that NO tonically inhibits ET-1 function, and in conditions of diminished NO bioavailability, the deleterious effects of unmitigated ET-1 actions result in vasoconstriction and eventually lead to vascular remodeling and dysfunction.”
In the following study the researchers concluded that homocysteine decreases bioavailable nitric oxide.
J Biol Chem. 1997 Jul 4;272(27):17012-7.
Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase.
Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J.
“Hyperhomocysteinemia is believed to injure endothelial cells in vivo through a number of mechanisms…Hcy affects the bioavailability of NO…”
Re: Some Interesting Connections
Hi
Annesse, have you looked at what is a normal CD8 level and whether it increases in response to a stimulus? It's not my area so hopefully it's an easy one for you to answer.
Leonard- if you have USD 31.50 buy a copy of Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-like Receptor-2. It's here- http://www.cell.com/immunity/abstract/S1074-7613(13%2900088-5?script=true .
I think it is a sublime piece of research. The gist of the article ,as I see it, is a chronic kidney disease changes the response of HDL so it limits NO, promotes inflammation and increases arterial blood pressure leading to impaired endothelial repair. This only happens in the subset of children and adults with kidney disease. The adrenals sit at the top of the kidney. If our adrenal glands are compromised by the health of the mother or developmental immaturity we will have insufficient vitamin A being processed in our very early life and the consequences are quite disastrous. The does not mean our adrenal system is permanently compromised but we can set up a cycle that we can't stop which doesn't arise in a healthy population. this may be where your observations about the gut have their origin.
Regards
Annesse, have you looked at what is a normal CD8 level and whether it increases in response to a stimulus? It's not my area so hopefully it's an easy one for you to answer.
Leonard- if you have USD 31.50 buy a copy of Abnormal High-Density Lipoprotein Induces Endothelial Dysfunction via Activation of Toll-like Receptor-2. It's here- http://www.cell.com/immunity/abstract/S1074-7613(13%2900088-5?script=true .
I think it is a sublime piece of research. The gist of the article ,as I see it, is a chronic kidney disease changes the response of HDL so it limits NO, promotes inflammation and increases arterial blood pressure leading to impaired endothelial repair. This only happens in the subset of children and adults with kidney disease. The adrenals sit at the top of the kidney. If our adrenal glands are compromised by the health of the mother or developmental immaturity we will have insufficient vitamin A being processed in our very early life and the consequences are quite disastrous. The does not mean our adrenal system is permanently compromised but we can set up a cycle that we can't stop which doesn't arise in a healthy population. this may be where your observations about the gut have their origin.
Regards
Re: Some Interesting Connections
Scott1 wrote:Hi
Annesse, have you looked at what is a normal CD8 level and whether it increases in response to a stimulus? It's not my area so hopefully it's an easy one for you to answer.
Hi Scott~ I am no expert by any means on this subject, but I believe CD8 levels would increase in response to a stimuli, such as EBV, in a healthy person, but if there is something "driving" persistent B cell activation and therefore "reactivation" of EBV you will see what is taking place in MS and other autoimmune diseases. For instance, in the following study the researchers concluded that B cell activation during flares drives frequent EBV reactivation in lupus.
LoS Pathog. 2011 Oct;7(10):e1002328. doi: 10.1371/journal.ppat.1002328. Epub 2011 Oct 20.
Exhausted cytotoxic control of Epstein-Barr virus in human lupus.
Larsen M, Sauce D, Deback C, Arnaud L, Mathian A, Miyara M, Boutolleau D, Parizot C, Dorgham K, Papagno L, Appay V, Amoura Z, Gorochov G.
“Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV)…EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.”
Persistent B cell activation and the subsequent reactivation of EBV could eventually deplete the T cells that attack virus infected cells--CD8+T cells. Patients with MS have been shown to have a deficiency of CD8+T cells (Pender, 2011). In the following study published in the Journal of Virology the researchers stated that chronic viral infections often result in ineffective CD8+T cell responses due to functional exhaustion or physical deletion.
J Virol. 2003 Apr;77(8):4911-27.
Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.
Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R.
“Chronic viral infections often result in ineffective CD8 T-cell responses due to functional exhaustion or physical deletion of virus-specific T cells…Persistent infection led to a disruption of the normal immunodominance hierarchy of CD8 T-cell responses seen following acute infection and dramatically altered the tissue distribution of LCMV-specific CD8 T cells in lymphoid and nonlymphoid tissues…antigen appeared to be the driving force for this loss of function, since a strong correlation existed between the viral load and the level of exhaustion. Further, epitopes presented at higher levels in vivo resulted in physical deletion, while those presented at lower levels induced functional exhaustion. A model is proposed in which antigen levels drive the hierarchical loss of different CD8 T-cell effector functions during chronic infection, leading to distinct stages of functional impairment and eventually to physical deletion of virus-specific T cells. These results have implications for the study of human chronic infections, where similar T-cell deletion and functional dysregulation has been observed.”
This reminds me of the recent study from Italy that stated EBV and MS were "relapsing together". I think there is a third party involved. One that is driving EBV and MS as well.
I think I have a pretty good idea of what it is (no, not vitamin B12), but I want to finish the homocysteine pathway and some other things vitamin B12 is involved in first.